Tretinoin, also called all-trans retinoic acid or Vitamin A Acid, is derived from Vitamin A by two oxidative steps. The first converts Vitamin A, which is an alcohol, to its aldehyde form while the second, subsequent oxidation converts the terminal carbon aldehyde group to a carboxylic acid group. The agent thus formed is known as Vitamin A Acid or all-trans retinoic acid, or simply tretinoin. The reactions are illustrated as: ##STR1##
Chemically, oxidation consists of a loss of electrons; reduction is the opposite: a gain of electrons. The oxidative process can involve atmospheric oxygen directly. Additionally, oxidation may also occur by a loss of electrons and without the addition or presence of oxygen in the final product, e.g., oxidation of ferrous chloride to ferric chloride.
Both types of reactions are important, but those involving atmospheric oxygen are more frequently encountered with pharmaceutical or cosmetic products. Oxidative reactions may involve both aqueous and nonaqueous ("oily") formulations. Generally, oxidative reactions depend on several factors such as:
(a) temperature PA1 (b) labile oxygen concentration, "labile oxygen" being considered oxygen that is readily releasable from its bound form; PA1 (c) catalysts that may be present, sometimes as formulation necessities, PA1 (d) pH, PA1 (e) light, and PA1 (f) concentration of the oxidizable ingredients. PA1 (a) ultraviolet or fluorescent lighting PA1 (b) oxygen (atmospheric or labile), and PA1 (c) temperature. PA1 (a) package the tretinoin-containing formulation in light PA1 (b) exclude air from randomly contacting the finished product; PA1 (c) formulate carrier vehicles for the tretinoin so as to exclude labile, oxygen containing ingredients whenever possible; PA1 (d) label the finished product so that it is stored within refrigerated conditions or conditions that mimick same and, PA1 (e) most importantly and most commonly, to include additives (antioxidants) in the formulation that retard oxidative degradation. PA1 (a) metallic sulfite salts, e.g., sodium sulfite and sodium metabisulfite; PA1 (b) cresol or toluene derivatives, e.g., benzoic acid, sodium benzoate, calcium benzoate, and butylated-hydroxytoluene; PA1 (c) ascorbic acid; PA1 (d) maleic acid; PA1 (e) propyl gallate, and PA1 (f) sodium formaldehyde sulfoxylate.
In sealed containers a reduction in the oxidative rate can be attained by lowering the temperature for most agents susceptible to oxidative degradation. The pH of the formulation is sometimes critical, since a number of oxidation-reduction processes are dependent upon hydrogen or hydroxyl ions and/or their ratio to one another.
Light often accelerates an oxidation process; storage of the finished product in dark containers frequently does much to retard oxidative reactions. Oxidative photolytic changes in some compounds create degradation by-products which function to propagate or catalyze the decomposition once started. Similar events, termed auto-oxidation, may occur even in the absence of light when susceptible materials are stored in the presence of air. The oxygen concentration of formulations (versus atmospheric oxygen) is a critical factor in many cases and often depends on the temperature of storage. Oxygen becomes more soluble in aqueous media as the temperature is lowered. Thus, oxygen dependent, oxidative reactions can sometimes proceed more rapidly at lower temperatures. Decomposition by oxidation often is a complicated process, with the overall rate dependent upon several factors, the relative importance of each being a function of the particular agent susceptible to oxidative degradation.
Tretinoin is an agent that is extremely sensitive to oxidative degradation, partially due to its high degree of unsaturation. Consequently, it easily undergoes rapid oxidation at ambient conditions. This ease of oxidation is a decided disadvantage, since continued degradation of tretinoin results in a total loss of its topically applied, therapeutic activity. Additionally, the oxidative lability of tretinoin has historically restricted its number dosage form.
Specifically, tretinoin is most susceptible to the following oxidative factors:
Of these factors, temperature per se appears to be the least critical since it requires at least one of the other factors to be present in order for it to exert significant degradation. Light, alone, or oxygen (atmospheric or labile) is capable of rapid, significant oxidation of tretinoin. Obviously, as the number of degradative factors concurrently present increases, so does the totality and rate of tretinoin's oxidative degradation, and loss of therapeutic efficacy.
In order to stabilize tretinoin in a dosage form suitable for topical application, it has been known to do one or all of the following procedures:
resistant containers;
Procedures (a) and (b) are most commonly accomplished by (1) packaging the formulation in metal or plastic threaded containers that seal tightly and preclude light, and (2) filling the formulation in the absence of air under yellow light, respectively.
The use of antioxidants has long been practiced to retard oxidation of tretinoin. Typical antioxidants used to retard tretinoin oxidation for topical application dosage forms have included:
With the possible exception of ascorbic acid, which does not lend itself for topical ophthalmic use due to its pH, all the listed antioxidants have been implicated with serious, sometimes irreversible cytotoxic reactions, viz., liver carcinoma in the case of the toluene and metallic sulfite salts. Consequently, the elimination of such antioxidants by a method that preserves the stability of tretinoin over a reasonable time period is advantageous.
The literature is extensive with documentation that application of topical products to intact dermis results in systemic absorption of the inactive formulation components (such as antioxidants) as well as active ingredients. When the integrity of the dermis is pathologically compromised, the systemic uptake of product ingredients is significantly enhanced.
Systemic uptake of formulation ingredients through topical application by the ophthalmic route is likewise extensively documented. Uptake is exhibited from both aqueous and oleaginous based formulations. The juxtaposition of a large number of blood vessels at the location where ophthalmics are applied favors rapid and significant systemic absorption of all formulation ingredients. As with compromised dermis, this absorption is greatly enhanced during pathologies of the eye and associated areas. An additional concern occasioned by the inclusion of antioxidant materials in ophthalmic preparations is their interference with the healing process associated with ocular tissue. Contemporary ophthalmological literature stresses the need to eliminate anti-microbial preservatives and other ancillary "pharmaceutical necessities" from ophthalmic medications whenever possible because of their demonstrated inhibition of the healing process.
If topical application of a product containing such antioxidants is practiced chronically and/or if the product is applied to large areas of the dermis, the uptake of these agents can be substantial with the potential consequence of severe, systemic, cytotoxic reactions.
It is, therefore, a primary object of this invention to attain a method of manufacture whereby tretinoin can be incorporated into a nonaqueous vehicle in such a fashion that it retains an acceptable range of potency over a reasonable time period--no less than about two years--without the use of antioxidants and without the need for refrigeration of the finished product. To avoid refrigeration promotes better patient compliances and does not limit geographical use of the product to those more affluent areas of the world where refrigeration is commonplace.
Topical application of tretinoin is indicated for at least two major pathological categories. Topical application to the dermis has proved beneficial for treatment of those surface eruptions and skin discolorations attributed to acne vulgaris and psoriasis. Topical application to the surface of the eye has been demonstrated to reverse the spread of certain selective surface disorders, such as corneal and conjunctival keratinization, which leads to irreversible blindness.